Department of Cancer Research, Max Delbrück Center for Molecular Medicine, 13215 Berlin, Germany;
Department of Cancer Research, Max Delbrück Center for Molecular Medicine, 13215 Berlin, Germany.
Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14421-14432. doi: 10.1073/pnas.1921139117. Epub 2020 Jun 10.
Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.
EB 病毒（EBV）是一种 B 细胞转化病毒，在免疫抑制条件下会导致 B 细胞恶性肿瘤。EBV 通过其潜伏膜蛋白（LMPs）和 EBV 核抗原（EBNAs）来协调 B 细胞转化。我们在这里鉴定了由 LMP1 诱导的小鼠 B 细胞淋巴瘤中的继发突变，以预测和鉴定转化过程中其他 EBV 基因的关键功能。我们发现早期 B 细胞因子 1（EBF1）的异常激活可通过抑制 LMP1 表达的 B 细胞向浆细胞分化来促进其转化。EBV EBNA3A 在 LMP1 表达的 B 细胞中模拟 EBF1 的活性，促进转化而抑制分化。在表达 LMP1 与 LMP2A 的细胞中，仅当 EBVNA2 靶标 Myc 也过表达时，EBNA3A 才会促进淋巴瘤的发生。总之，我们的数据支持这样一种模型，即 LMP1、LMP2A 和 EBNA2 的促增殖活性与 EBNA3A 介导的抑制终末浆细胞分化相结合，可显著控制 EBV 介导的 B 细胞淋巴瘤的发生。
